Iontophoresis disc pain blocker

ABSTRACT

Treatment of pain syndromes utilizes a topical polypharmaceutical preparation of phenoxybenzamine, ketamine, gabapentin, nifedipine, carbamazepine, or combinations of them. Other suitable components are blockers of sympathetic alpha 1, 2 and other receptors, NMDA receptor blockers, GABA receptor blockers, AMPA receptor blockers, nitric oxide synthase receptor blockers, calcium channel blockers, ACDP receptor blockers, prostaglandin and leukotriene blockers, substance P blockers, bradykinin and neurotenin as well as other peptide blockers, and TNF alpha blockers. Recommended delivery is by locating a predetermined neurodermal point and locating a gel patch over the predetermined neurodermal point. Iontophoresis then delivers the pharmaceutical agent from the gel patch.

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] Not Applicable

STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT

[0002] Not Applicable

BACKGROUND OF THE INVENTION

[0003] 1. Field of the Invention

[0004] The invention generally relates to surgery and to a method andmeans for introducing or removing material from the body for therapeuticpurpose. More specifically, the invention relates to apparatus andmethod in which electrical energy is applied to the body, such as byiontophoresis. Similarly, the invention may have application in a methodand apparatus for surgery in which material is introduced into orremoved from a body orifice or inserted or removed subcutaneously otherthan by diffusing through skin. The invention has application to amethod of enhanced absorption of therapeutic material usingiontophoretic treatment. A specific focus is blocking pain by precisionadministration of suitable treatment.

[0005] 2. Description of Related Art Including Information DisclosedUnder 37 CFR 1.97 and 1.98

[0006] Treatment of pain in humans is a topic of increasing researchemphasis. One promising approach is by use of topical cocktails ofingredients for blocking pain from many origins. Rather than offeringmere additive results, the multi-component cocktail of ingredientspromises an unexpectedly high level of efficacy. Another developingapproach is the use of improved delivery systems, which often can beused for the administration of treatments for diseases and conditionsnot solely limited to pain. Such delivery systems employ, gels creams,ointments, patches, bioadhesives, and iontophoresis that can deliver avariety of pharmaceuticals, alone or in combined administration. Theseapproaches are exemplified in the following patents.

[0007] U.S. Pat. No. 5,900,249 to Smith discloses treatment of specifictypes and causes of pain by administration of a multi-component topicalcomposition. For example, one component offers anesthetic pain reliefthat masks pain but does not correct the underlying cause. Anothercomponent reduces the sensation of pain by alleviating the physiologicaland neurotransmitter etiology of the pain. Each of the various activecomponents functions differently in order to treat pain comprehensively,regardless of causes. Multiple components include, first, a vasodilatingagent such as nifedipine; second, an antiinflammatory agent to reducepain mediated by prostaglandins; third, a membrane stabilizing agentsuch as carbamazepine; and fourth, seratogenic and nonadrenergicreuptake inhibitor. These may be supplemented with a topical anestheticand an anti-inflammatory steroid. These medications are delivered in agel, ointment, or cream.

[0008] U.S. Pat. No. 5,837,289 to Grasela discloses a general purposedelivery system that employs transdermal delivery of medication in apatch. Iontophoresis is useful with the medication in the patch toincrease skin permeation. A topical delivery system may use a creamcarrying the desired medication plus penetration enhancers.

[0009] U.S. Pat. No. 6,210,394 Demopulos discloses a cocktail of painblocking agents for topical administration by irrigating with combinedinhibitors for both pain and inflammation. The treatment addresses paincaused by multiple distinct sources of pain, including prostaglandin,bradykinin, histamine, and serotonin. Each source can be inhibited byapplication of the corresponding receptor antagonists. The cocktail ofanti-pain/anti-inflammation agents can be composed of fourteen classesof receptor antagonists and agonists, plus optional anti-spasm agents.An aspect of the treatment is a resulting synergy in certaincombinations, believed to result from cross talk between varioussignaling pathways.

[0010] The practice of iontophoresis is useful to deliver a drug to asubject by driving charged ions of the drug through the skin of thesubject by applying an electric potential. The effective component ofthe drug must carry a charge, and the electrical apparatus must bepolarized in the proper direction to deliver the charged component. Forexample, a patch containing a drug with positive charge is applied tothe skin of a subject. The patch is connected to the iontophoreticdelivery system at the positive electrode. A negative electrode isconnected elsewhere to the subject to complete a closed pathway for theelectric current.

[0011] A recent and representative discussion of iontophoresis appearsin U.S. Pat. No. 6,235,013 to Tapper. An iontophoretic patch andadministration system employ alternating current of low frequency inorder to avoid problems of skin damage and pH imbalance duringadministration.

[0012] Electrical probes can detect numerous topical points in the skinthat show a dramatic drop in skin resistance, as measured in meg ohms.These points are neurodermal points and are identified as Langerhanscomplexes. They have a pattern in dermis tissues much like a grid. Thepresence of these neurodermal points has been known for a long time. Inancient China, equivalent points were known as points of Chi or energy,and in India they were called Prahna. In fact, they are a normal complexof afferent and efferent A delta sensory myelinated nerves, smallunmyelinated “C fibers,” and tiny endocrine organelles. Such structuresare capable of releasing NO, nitric oxide, and gamma amino butyric acid(GABA). They are also capable of locally releasing a variety ofsubstances. These include Ca⁺⁺ ions via the NMDA,aminocyclopentane-1,3-dicarboxylate (ACPD) receptors; substance Ppeptide; alpha-amino-3-hydroxy-5 methyl-4-isoxazolepropionic acid (AMPA)receptors; and glutamate.

[0013] Persons born without Langerhans complexes in the superficialdermis cannot suffer pain. Thus, the pain process requires theprojection of painful nociceptive afferents from superficial and deepstructure onto the dermal grid of the Langerhans network. The afferentmodulation at this level of preprocessing determines if there is painfulperception at each dermatome with central projection of these neuralholograms to ever-higher levels of modulation at the dorsal horn,substantia gelatinosa areas V to IX, rostrally to the thalamus andtectum of the midbrain and onto the cortical modulation. This processdetermines patterns of proprioceptive interpretation and, thus, musclestatic and dynamic firing patterns. Spasm is modulated via red fibertonic muscle fibers that cause spinal and joint subluxation, and furthernociceptor stimulation via A delta afferent pain fibers and C fiber painafferents. The earliest pattern on EMG is spectral imbalance in surfaceEMG with non-physiologic phase shifts in axial paraspinal muscle firingand increased greater than 400 Hz efferents to the spinal myotome orperipheral muscles.

[0014] A number of known electrical probes employ an electric current orresistance measurement to aid in administering drugs or performing amedical procedure. A representative example appears in U.S. Pat. No.3,862,162 to Colyer, which combines a hypodermic needle with anelectrical probe. The probe is useful to locate a nerve, which can betreated by injecting a selected medicament through the needle. U.S. Pat.No. 5,853,373 to Griffith et al. suggests the use of a similar needleand probe combination in order to locate a nerve for administration ofanesthetic. U.S. Pat. No. 5,284,153 to Raymond et al. suggests using anerve stimulator either to assist in administration of regionalanesthesia or to guard against cutting specific nerves during surgery.

[0015] Thus, a technology is known for locating a nerve or neurodermalpoint by electrical detection, and this has aided in administeringcertain types of treatments or drugs. However, this technology has notbeen adapted to improve the efficiency or effectiveness iontophoresis.In particular, the method of this invention improves iontophoresis byfirst using a probe to locate a neurodermal point, and then placing apatch containing the drug over the located point, and driving the druginto the subject by applying an electrical current across the patch andthe subject's skin at the located point. The effectiveness of thetreatment is improved, while the required quantity of drug often issubstantially decreased. With a lower quantity of the drug required tobe administered for effective treatment, the patient benefits byreduction in side effects. This results in an improved overallefficiency and effectiveness of treatment.

[0016] Further improvements in treatment are possible by selecting andformulating a polypharmaceutical preparation for application by topicalmeans, which may include iontophoresis. The placement of aniontophoretic patch on a preselected neurodermal point, located by useof a probe, further improves the treatment.

[0017] An improved polypharmaceutical preparation can be formulated bythe suitable selection and combination of an array of drugs. Thepreferred candidates include ketamine, which topically blocks the NMDACa⁺⁺ channels. Gabapentin also is a glutamate antagonist. Carbamazepineis an AMPA (Na⁺ channel) receptor blocker, as is gabapentin. The 10-11epoxide is the active molecule that modulates C fiber afferents at theLangerhans complex. Carbamazepine blocks peripheral sympathetic nervereceptors via the voltage-dependent sodium channels, in the same manneras it blocks these receptors in the dorsal root ganglion (DRG).Clonidine is an alpha 2 blocker that similarly blocks the alpha 2receptor. Phenoxybenzamine is an alpha 1 agonist. It has much more powerto block dorsal ganglionic afferents that synapse with the interneuronsof the wide range neurons of areas V to IX of the dorsal horn, beforeascending up Lissauer's spinothalamic tract, carrying afferent painfulstimuli to the thalamus. Nifedipine is useful for non-NMDA,voltage-sensitive calcium-channel blockade, which down regulates nitricoxide (NO) synthesis.

[0018] Pluronic lecithin organogel (PLO), topical vehicle allows theabove pharmaceuticals to penetrate to the dermis and modulate upregulated activity in all these pathways that cause acute and chronicpain, modulation at the periphery.

[0019] There are three phases of rehabilitation: phase one—increasedactivity at the same pain level; phase two—decreased pain at the sameactivity level; and phase three stabilization—damping of the sine wavefluctuation status with less severe and frequent flare-ups in pain,spasm and deconditioning. Such topical pharmacotherapy has proveneffective on numerous patients at accomplishing benefits at all threephases of rehabilitation. Static and dynamic spasm is reduced, anddynamic eccentric-concentric contraction is restored to proper in-phase180-degree muscle firing for oppositional muscles across the paraspinalmyotomes and peripheral muscles. Restoration of oxygenation, withprevention of vasoconstriction all improved tissue healing and reducedlow oxygen tension dependant induction of fibroblast collagen IIIgeneration that with later remodeling will produce adhesions and neuralentrapments. In other words, barriers to movement, vasoconstriction, andhealing are removed via topical peripheral pharmacological blockade. Theneural holographic image of the pain is blocked before it can beprojected rostrally to the thalamus and cortex, with resultant musclefiring abnormalities, postural and dynamic changes and vasoconstrictivechanges with subsequent deconditioning and development of atrophy.

[0020] There are estimated to be 50 million Americans with partial ortotal disability due to chronic pain. The world market is estimated tobe about $7.7 billion for analgesics in US dollars. The American PainSociety estimates 45% of the population seeks medical help forpersistent pain at some point. The cost to American workers andcompanies, including lost workdays and physician visits, is in excess of$100 billion per year in America, alone.

[0021] New scientific evaluation tools such as Quantitative SensoryNerve Threshold Testing using the MediDx 7000 to map sensory nerve andsympathetic nervous function can add the dimension of quantitativeassessment of the patient's neuropathologic improvement ordeterioration. Diagnostic spinal ultrasound (DSU) also will demonstrateimprovements or deteriorations with changes to perineural edema andmyofascial edema up to six inches on either side of the spinal cordsagittal plane, as well as changes in posterior element facetarthropathy. Application of these technologies can verify the efficacyas not only altering the patient's reported pain and loss of function,but also the quantitative physiological parameters of improvement in Adelta and C fiber physiology, as well as joint, muscle and soft tissueedema and inflammatory change.

[0022] Most pain has a strong neuropathic component. Currentover-the-counter (OTC) preparations are not benign. Thus, saferapproaches without systemic side effects are required. Delivery of theseeffective but toxic or sedating pharmaceuticals avoids systemic effectsand is very useful, safer and gives an element of control and validationback to the sufferer. An effective topical preparation can significantlyreduce reliance on OTC preparations and on more powerful, orallyadministered, centrally acting pharmacotherapies that carry with themsignificant risks and side effects. More rapid recovery and lower use oforal and injected drug therapies are obvious benefits, leading to morerapid reconditioning, and maintaining fitness for duty at work andfitness for recreation. Suppressing the image of pain in the peripheralLangerhans dermal complexes results in suppression of the primary painimage at its primary projection sites of the Langerhans complex network.Such a polymodal pharmcotherpeutic management plan will prove to be akey step in all forms of pain control in the 21st century.

[0023] It would be desirable to improve the efficiency of treatmentusing iontophoresis by locating effective treatment sites. In addition,it would be desirable to formulate and administer more effectivetreatments for pain syndromes, both by addressing multiple pathways ofpain propagation and administering such treatment by improved methods.

[0024] To achieve the foregoing and other objects and in accordance withthe purpose of the present invention, as embodied and broadly describedherein, the method and apparatus of this invention may comprise thefollowing.

BRIEF SUMMARY OF THE INVENTION

[0025] A general object of the invention is to provide a new andimproved composition and method of treatment of pain, utilizing topicalpreparations.

[0026] Another object is to provide a composition and method of the typedescribed which provides the desired therapeutic response throughtopical administration in the form of cream-gel preparation, spray oraerosol, and topical iontophoresis methodology patch.

[0027] The invention provides a composition and method of treatment foralleviating pain. A solution of pharmaceuticals includingphenoxybenzamine, ketamine, gabapentin, nifedipine, and carbamazepine inPLO carrier or other suitable topical preparation vehicle is appliedtopically to the painful region of the skin.

[0028] The invention is derived from research and observations showinglocal anesthetic blockade at the Langerhans complex network map of apain-projected distribution. The mechanisms for pain modulation in thedermis provide a new theory of pain gate and prespinal cord modulationthat can block afferent pain perception and the attendant reflex spasm,vasoconstriction, and atrophic and deconditioning effects that canresult from a projected neural holographic image.

[0029] According to the invention, a method of administering apharmaceutical agent suited for iontophoretic delivery to a human oranimal subject is performed by, first, performing a point locating stepby locating on a subject to be treated a preselected neurodermal pointfor receiving the pharmaceutical agent. Second, a patch application stepis performed by applying to the subject, over the preselectedneurodermal point, an iontophoretic patch containing the pharmaceuticalagent to be administered. Third, a delivery step is performed byapplying an electrical potential across the iontophoretic patch and thesubject and delivering the pharmaceutical drug from the patch to thesubject at the neurodermal point by iontophoresis.

[0030] According to another aspect of the invention, apolypharmaceutical composition for treating chronic pain by producing ablockade of the initiation and propagation of the pain stimulus in theLangerhans and other neuroendocrine vascular structures of thesuperficial and deep dermis is composed of, in combination, at least twopharmaceutical agents selected from the group consisting of an NMDAreceptor blocker, a GABA receptor blocker, an AMPA receptor blocker, anitric oxide synthase receptor blocker, a calcium channel blocker, anACDP receptor blocker, a prostaglandin blocker, a leukotriene blocker, asubstance P blocker, a bradykinin blocker, a neurotenin blocker, apeptide blocker, a TNF alpha blocker, a sympathetic alpha 1 receptorblocker, a sympathetic alpha 2 receptor blocker, and a non-NMDAcalcium-channel blocker.

[0031] According to still another aspect of the invention, a method oftreating pain by producing a blockade of the initiation and propagationof the pain stimulus in the Langerhans and other neuroendocrine vascularstructures of the superficial and deep dermis, is performed through anadministration step by topically administering to a person in need ofsuch treatment an effective dosage of a combination of at least twopharmaceutical agents selected from the group consisting of an NMDAreceptor blocker, a GABA receptor blocker, an AMPA receptor blocker, anitric oxide synthase receptor blocker, a calcium channel blocker, anACDP receptor blocker, a prostaglandin blocker, a leukotriene blocker, asubstance P blocker, a bradykinin blocker, a neurotenin blocker, apeptide blocker, a TNF alpha blocker, a sympathetic alpha 1 receptorblocker, a sympathetic alpha 2 receptor blocker, and a non-NMDAcalcium-channel blocker.

[0032] According to a further aspect of the invention, a method oftreating pain in a human or animal subject by administering acombination of preselected effective pharmaceutical agents in ansuitable dosage to treat a subject in need thereof, is carried out by,first, performing a point locating step by locating a predeterminedneurodermal point associated with the pain. Second, the preselectedpharmaceutical agents for treating pain are provided in a gel patchsuited for delivery by electrically driving charged ions of thepharmaceutical agents from the path and into the subject. Third, anapplication step is performed by applying the provided gel patch to thepredetermined neurodermal point on the subject. Fourth, a delivery stepis performed by delivering the selected pharmaceutical agents from thepatch to the subject by electrically driving charged ions of thepharmaceutical agents into the subject.

[0033] The accompanying drawings, which are incorporated in and forms apart of the specification illustrates preferred embodiments of thepresent invention, and together with the description, serves to explainthe principles of the invention. In the drawings:

BRIEF DESCRIPTION OF THE SEVERAL VIEWS OF THE DRAWINGS

[0034]FIG. 1 is a schematic diagram of a method of delivering apharmaceutical agent.

[0035]FIG. 2 is an isometric assembly view of a multi-layeriontophoretic patch disc with a wafer battery and layers ofpharmaceutical gel and buffers, showing the side and bottom portions ofthe disc, and with portions of a contact ring and dielectric ring brokenaway for clarity.

[0036]FIG. 3 is an isometric view of the patch disc of FIG. 2, showingthe side and top portions of the disc.

DETAILED DESCRIPTION OF THE INVENTION

[0037] A first aspect of the invention is a method of administering apharmaceutical drug suited for iontophoretic administration. Accordingto the method, first locate a predetermined neurodermal point selectedfor its suitability for receiving the pharmaceutical drug. Second, applyan iontophoretic patch to the predetermined point. Third, apply anelectrical potential across the patch and the subject to deliver thepharmaceutical drug to the subject by iontophoresis. Related aspects ofthis invention include the composition and structure of an iontophoreticdisc or patch for use in the method.

[0038] A second aspect of the invention is a novel composition fortreating chronic pain by producing a blockade of the initiation andpropagation of the pain stimulus in the Langerhans and otherneuroendocrine vascular structures of the superficial and deep dermis.

[0039] A third aspect of the invention is a method of treating pain bytopically administering the novel composition of pharmaceutical agents,thereby producing a blockade of the initiation and propagation of thepain stimulus in the Langerhans and other neuroendocrine vascularstructures of the superficial and deep dermis.

[0040] A fourth aspect of the invention is a method of administering thecombination of pharmaceutical agents to treat pain, in which thecomposition is made available in an iontophoretic gel patch that isplaced by locating a predetermined neurodermal point associated with thepain. The patch is applied to the predetermined neurodermal point.Iontophoresis delivers the pharmaceuticals by driving charged ions ofeffective agents into the patient.

[0041] When used in the treatment of pain, the compositions, methods,and apparatus of this invention will extinguish the neural hologram ofthe painful image, topically. The composition is comprised ofpharmacologically acceptable salts of active compounds comprised ofnon-toxic acid addition salts and inorganic acids. Within the UnitedStates, “pharmacologically acceptable salts” preferably are thoseapproved for use on humans by the United States Food and DrugAdministration (FDA), to the extent such approval currently is requiredor may be required in the future. FDA approval is desirable in thosegeographic areas under the jurisdiction of the FDA for the treatment ofhumans, but it is not a limitation on the scope of the invention.

[0042] A unique composition and dosage form have been developed for thetopical treatment of refractory neuropathic pain. The composition is atopical pharmaceutical composition for extinguishing the neural hologramof a painful image. The composition is a combination of ingredients thatblock various released agents that trigger the pain sensation. Thereleased agents are NO (nitric oxide); GABA (gamma amino butyric acid);Ca++ ions via NMDA; ACPD (aminocyclopentane-1,3-dicarboxylate);substance P peptide; AMPA (alpha-amino-3-hydroxy-5methyl-4-isoxazolepropionic acid); and glutamate. Broadly, the blockingagents target the following receptors: sympathetic alpha 1,2; NMDA;GABA; AMPA; nitric oxide synthase; calcium channel; ACPD; prostaglandinand leukotriene; substance P; bradykinin, neurotenin and peptide; andTNF alpha.

[0043] Selected components are combined and delivered in a topicalvehicle, preferably pluronic lecithin organogel (PLO). Specificcomponents are phenoxybenzamine; ketamine; gabapentin; nifedipine;carbamazepine; and clonidine. Methods of topical application are ascream, gel, ointment, spray or patch, especially by iontophoresisdelivering the components through an iontophoretic patch.

[0044] A preferred composition consists of three selected activepharmaceutical agents: ketamine HCl USP, gabapentin, andphenoxybenzamine HCl. These three agents are incorporated into pluroniclecithin organogel (PLO) to facilitate transdermal administration.

[0045] The concentration by volume of the active pharmaceuticalcomponents are preferred to be approximately 2% phenoxbenzamine, 5%ketamine, and 5% gabapentin. The concentration of constituents inpercent of solution may be varied for specific types of pain blockade,so as to obtain a desired therapeutic response for a particular patientpopulation. These components are mixed in a controlled environment.Precautionary measures should protect pharmaceutical workers from activeingredients that may become airborne or be topically absorbed. In theUnited States, OSHA complaint safety procedures should be followed.

[0046] The composition includes a pharmaceutically acceptable liquidcarrier serving as a vehicle, including a biphasic complex of lecithinand organogel, for molecular egression across the epidermis to thesuperficial and deep dermis where neuroendocrine vascular structuressuch as the Langerhans bodies reside. PLO is a phospholipid liposomalmicro emulsion used for transdermal drug administration. It has twophases:

[0047] (1) Oil Phase: The oil phase is lecithin/isopropyl palmitatesolution. Lecithin rearranges the horny layer of the skin. Isopropylpalmitate is a solvent and penetration enhancer. Sorbic acid is apreservative.

[0048] (2) Water Phase: The water phase is the pluronic gel. Pluronicf127 NF is a commercial surfactant. Potassium sorbate NF is apreservative. Purified water is a solvent. The active agents areincorporated into the PLO gel and a stable emulsion is formed throughsheer force. The concentration of the active agents in the formulationmay be adjusted as to obtain the optimal therapeutic response.

[0049] A composition of the active agents and carrier is preparedaccording to the following procedure. First, triturate the ketamine HClUSP, gabapentin, and phenoxybenzamine HCl, together using geometricdilution. Second, solubilize the chemical in purified water, USP. Third,combine the solubilized chemical with the lecithin/isopropyl palmitatesolution and mix well. Fourth, add pluronic F127 20% gel in smallincrements to bring to desired volume. Fifth, mix at high rate of speedin electronic mortar and pestle to form smooth creamy gel.

[0050] Once prepared, the solution of pharmaceutical can be administeredtopically to the region of pain either by the patient or by a heath careprovider. The form of dosage for topical administration includessolutions, suspensions or emulsions of the active components in a liquidcarrier in the form of cream, gel, ointment, and topical iontophoresismethodology patch technology. Suitable carriers include pluroniclecithin organogel (PLO) or other suitable suspensions or carriers. Whenthe dosage form is a topical cream-gel suspension or topical patchmethodology, it may contain preservatives, stabilizers, emulsifiers orsuspending agents, wetting agents, salts for osmotic pressure orbuffers, as required. When the dosage form is as a pressurized spray oraerosol, the solution is contained in a pressurized container with aliquid propellant such as dichlorodifluroro methane or chlorotrifluoroethylene. If administered from a pump container, the solution willinclude a buffer salt solution with preservatives, stabilizers,emulsifiers or suspending agents, wetting agents, and salts for osmoticpressure or buffers, as required.

[0051] When the composition is administered in the form of topicalgel-cream, spray, or topical iontophoresis gel patch, the time of repeatapplication will vary from every six to twelve hours for the gel-creamand spray to several days for the topical iontophoresis gel-patchdelivery methods. Occlusion with a barrier ointment or physical barriersuch as hypoallergenic membrane may also be administered after topicalapplication of the gel-cream or spray to increase efficacy andpenetration of the pharmaceutical to active pharmaceutical sites in thedermis.

[0052] The following examples show the efficacy of the composition intreating chronic pain.

EXAMPLE I

[0053] A 44-year old female had a history of neck and upper back injury,with secondary chronic regional pain syndrome (CRPS), with continuoussymptoms for 24 months post trauma, especially with activity andmovement. The patient was treated with the topical polypharmaceuticalpreparation in PLO, and noted an immediate reduction in pain, increasedmovement with reduced activity induced pain and reduced referred painand numbness into her upper extremities. Repeated use of the preparationresulted in continued accumulative reduction in pain and improved rangeof motion of the neck, upper back and upper extremities, and asignificant reduction in a hypersensitivity of the skin to even lighttouch, which had been noted prior to treatment. The patient wasmaintained on the topical blockade on a permanent basis.

EXAMPLE II

[0054] A 49-year old male had a motor vehicle accident, with two levelbulging cervical discs, and musculoligamentous instability at multiplelevels in his cervical spine with pain twelve months followingdeceleration injury. Utilizing topical application of the preparationtwo to three times per day, he achieved a significant reduction in painimmediately, with improved range of motion. Accumulative benefit infurther reduction of pain, improved range of motion and reduction oftopical hypersensitivity to touch and activity were noted, withcontinued use. He was continued on the preparation on a permanent basis,during the rehabilitation and contributed greatly to his achievinghigher spinal muscular tone and dynamic motor control, and lessinterference with activities of daily living (ADLs).

EXAMPLE III

[0055] A mid-twenties female patient with a lifting injury, resulting inbulging lumbar disc, myofascitis, and perineural as well as facetarthropathy identified on diagnostic spinal ultrasound (DSU) and MediDx7000 quantitative sensory nerve conduction threshold testing, wastreated with the topical preparation. She noted immediate reduction inpain with application and accumulative pain reduction, with improvedlower extremity temperature, reduction in muscle spasms, and improvedspinal postural and dynamic motor control. Accumulative improvementswere noted in all the above areas. She was continued on the topicalpreparation during the entire period of her rehabilitation, and itcontributed greatly to reduction in barriers to reconditioning, andmaintaining increased activity levels, with reduction in problems withADLs.

[0056]FIG. 1 illustrates an overview of the method practiced in thisinvention 10. The preferred methodology 10 for administering thetreatment is to perform a locating step 12 to identify neural points.For this purpose, a suitable instrument is an electronic point finderthat has the capability to identify nerves or neural points, which canbe detected by their relatively lower electrical resistance compared tosurrounding body or skin areas. U.S. Pat. No. 5,284,153 to Raymonddiscloses one such point finder and is incorporated by reference hereinfor disclosure of such devices. A variety of such instruments arecommercially available and often combine functions of selectivelydetecting a nerve and selectively applying an electrical current tostimulate the nerve.

[0057] Once the desired nerve or nerves are identified, a preselectedcomposition of pharmaceuticals 14 is prepared for an administration step16. Administration may be topical, by methods including gel 18 or spray20. Iontophoresis is a preferred method. The composition is applied to apatch 22 for iontophoretic administration. Suitable patch structuresinclude both single and multi-layered gel matrix discs. For example, apatch may be arranged with one or more layers of pH bufferedelectrolytes between drug layers. Ionotphoresis 24 delivers the drugs byapplication of tiny unipolar or switchable bipolar micro amperagecurrent to the gel disc over the next 24 to 36 plus hours, producingblockade to the excessive nerve firing.

[0058] As a result of practical patient experience, two components havebeen found to work well for delivery by iontophoresis. These areketamine, which is an NMDA receptor blocker, at 2 to 4% or higher, andclonidine, which is an alpha 1 sympathetic receptor blocker, at 0.2 to0.4% concentration, unbuffered. Both have positive polarity, and arepositive charged. Selection of positive polarity would push the drugalong the pathway of least resistance, finding the involved overactivenerve fibers; and pain blockade would occur.

[0059] Several different methods or devices can perform iontophoreticadministration. The composition can be administered by use of a knownpersonal iontophoretic device. Alternatively, a treatment disc can bepreloaded with gel layers of this or other listed and potentialpharmaceuticals. The treatment disc 50 of FIG. 2 includes a wafer microbattery 56 for applying an electrical potential through the gel layersand across the skin of the patient. Such a treatment disc would releasethe pharmaceuticals over the identified skin surface and into thepreviously identified nerves that are causing the local pain responseand contributing to the level one skin-spinal nerve root-paraspinalganglionic pain hologram.

[0060] A variety of point finders are known and may be used to identifythe nerve to be targeted. Two types of point finders are commerciallyavailable and are preferred choices.

[0061] Type 1—Acupuncture Point Finder:

[0062] This type of point finder measures electrical resistance byapplying a small test current between positive and negative electrodes,which typically are in close proximity to each other on the tip of aprobe. A light or sound indicates when a nerve or other pathway ofreduced skin resistance has been found. Some of these devices, such asthose produced by Siemens Scientific, can identify the drop of skinresistance in mega ohms.

[0063] Type 2—Motor Stimulation Nerve Finder:

[0064] This type of point finder is a nerve stimulator. A surfaceelectrode is applied along the skin to identify a current path, and anelectrical signal is applied to produce a muscle response. Severaltypical types of signals are used. These are known as a 50 to 100 Hztentanic stimulus, a DBL burst, a Train-Of-Four stimulus, or a Twitchstimulus. These same types of signals are commonly used in painfacilities to identify nerves before selective nerve root blocks, afterproducing a muscle response along the neurovascular bundle.

[0065] A gel disc as shown in FIG. 2 may be prepared for theiontophoresis pain blockade. The disc 50 includes a patch composed of amultilayer structure in which each of the three pharmaceutical agents isin a separate layer 54. Each layer of an active agent is separated fromany other layer of active agents by an interposed layer of electrolytebuffered gel 52.

[0066] In order to deliver the composition to a patient using electricalassistance, the gel disc is connected to a current source such as abattery 56. A first pole of the current source may contact the gelpatch, and a second pole may contact the skin of a patient. For example,in the view of FIG. 2, the first pole 58 may be the lower face of thedisc battery. This battery contact face 58 is positioned in electricalcontact with an outer face or top of the gel disc so that current canflow through the patch between the battery and the patient's skin. Theopposite or second pole 60 of the current source may be the upper faceof the disc battery. This battery contact face 60 is positioned inelectrical contact with a peripheral portion of the disc, such as ring62 that is in electrical contact with the skin of the patient when thepatch is used. The two poles are in a closed circuit formed when thedisc is applied to the patient's skin.

[0067] A peripheral ring 62 is the preferred configuration of theskin-contacting portion of pole 60. However, regardless of its shape,the contact 62 should be located at an offset position from the gelpatch so that current flows through the patient's skin in order tocomplete the circuit. A concentric dielectric insulating ring 64 lieswithin the contact ring 62. It insulates both the wafer battery 56 andthe gel disc 52,54 from the second pole of the battery. This insulatorensures that the two poles of the battery cannot form a closed circuitwithout an external current pathway.

[0068] According to known practice, the central disc would be the polechanged to the same charge as the pharmaceuticals to be administered,i.e., a positive pharmaceutical is delivered by a positive charge on thedisc surface in contact with the gel disc. As shown in FIG. 3, thesecond pole 60 of battery 56 is electrically connected to the outsidering 62, such as by a contact extension 65 that can be displacedsufficiently to allow the battery to be installed or removed from thedisc. The direction of current flow can be changed by such simplemeasures as reversing the battery 56 on the patch. Thus, in a basicembodiment as illustrated in FIG. 2, the polarity of the patchcorresponds to which face of the battery is applied to the top of thepatch.

[0069] A preferred patch is illustrated in FIG. 3, in which the patchstructure 50 includes a processor 66 embedded in the disc structure. Theprocessor may be associated with control circuitry operated byuser-selected control switches. The desired control switches cause theprocessor to vary four operating parameters. A first switch 68 selectswhether the current is unipolar or bipolar. A second switch 70 selectsthe direction of current flow, which is indicated as positive ornegative. A third switch 72 selects between a relatively lowermicro-amperage current and a higher micro-amperage current. A fourthswitch 74 selects whether the circuitry delivers straight DC current orpulsed DC current. These operating parameters are selectively adjustedaccording to the drugs being administered and other specific factorsdependent upon the conditions of administration. A supervising physicianbest can advise the patient of the preferred settings.

[0070] The gel disc is applied to a subject, preferably over a preciselylocated point identified by use of a point finder, as described. Thebattery or other current source delivers charged ions of the treatingpharmaceuticals from the gel disc and into the subject's skin. Placingthe disc over a neurodermal point provides an especially effectivelocation for delivery of the treatment, because electrical resistance ismeasurably lower at such points. A lower electrical resistance at theneurodermal point will result in greater delivery rate of thepharmaceutical into the subject.

[0071] The use of a point finder to locate the nerve or nerves in needof treatment allows the treatment to be delivered precisely, thusproducing an effective treatment. Further, this mode of treatmenteliminates the prior practice of applying a topical treatment oversubstantial areas not in need of treatment. Thus, the patient benefitsby receiving a quick and effective treatment at the precise location inneed of treatment, without application of excessive quantities of theactive agents. In these circumstances, side effects of the active agentsare minimized.

[0072] Although the gel disc preloaded with a composition for treatingchronic pain is an especially effective combination for delivery to aprecisely located neurodermal point, this method of delivery can beadditionally applied with still other pharmaceutical compositions.Accordingly, it is anticipated that this method is useful with any drugor medicament heretofore known or later discovered that is capable ofdelivery by iontophoresis.

[0073] Another preferred composition consists of selected blockers ofNMDA receptors and alpha 1 receptors. The active pharmaceutical agentsof this composition are dextromethorphan; clonidine, usuallyadministered as clonidine hydrochloride USP; magnesium chloride,available as a hexahydrate USP; and amantadine, available as amantadinehydrochloride.

[0074] A mixture of these agents is administered by the previouslydescribed methods of FIG. 1. A remarkably effective technique ofadministration is to locate a suitable administration site by using anelectronic point finder. A mixture of these agents, suitable foradministration by injection, is placed subcutaneously 26, such as byinjection at one or two sites near the preselected point. This simpleadministration has been found to high effective. The results arecomparable to a neural dermal block, which is previously unknown forsuch topical treatment.

[0075] The forgoing is considered as illustrative only of the principlesof the invention. Further, since numerous modifications and changes willreadily occur to those skilled in the art, it is not desired to limitthe invention to the exact construction and operation shown anddescribed, and accordingly all suitable modifications and equivalentsmay be regarded as falling within the scope of the invention.

1. A method of administering a pharmaceutical agent suited foriontophoretic delivery to a human or animal subject, comprising: first,performing a point-locating step by locating on a subject to be treateda preselected neurodermal point for receiving the pharmaceutical agent;second, performing a patch application step by applying to the subject,over the preselected neurodermal point, an iontophoretic patchcontaining the pharmaceutical agent to be administered; and third,performing a delivery step by applying an electrical potential acrossthe iontophoretic patch and the subject and delivering thepharmaceutical drug from the patch to the subject at the neurodermalpoint by iontophoresis.
 2. The method of claim 1, wherein thepharmaceutical agent is selected from the group consisting of an NMDAreceptor blocker, a GABA receptor blocker, an AMPA receptor blocker, anitric oxide synthase receptor blocker, a calcium channel blocker, anACDP receptor blocker, a prostaglandin blocker, a leukotriene blocker, asubstance P blocker, a bradykinin blocker, a neurotenin blocker, apeptide blocker, a TNF alpha blocker, a sympathetic alpha 1 receptorblocker, a sympathetic alpha 2 receptor blocker, a non-NMDAcalcium-channel blocker, and combinations thereof.
 3. The method ofclaim 2, wherein the pharmaceutical agent is carried in a topicalvehicle comprising a pluronic lecithin organogel.
 4. The method of claim1, wherein the pharmaceutical agent is selected from the groupconsisting of ketamine, gabapentin, carbamazepine, clonidine,phenoxybenzamine, nifedipine, and combinations thereof.
 5. The method ofclaim 4, wherein the pharmaceutical agent is carried in a topicalvehicle comprising a pluronic lecithin organogel.
 6. The method of claim1, wherein the pharmaceutical agent comprises phenoxbenzamine, ketamine,and gabapentin in an approximate quantity ratio of 2:5:5.
 7. The methodof claim 6, wherein the pharmaceutical agent comprises by volumeapproximately 2% phenoxbenzamine, 5% ketamine, and 5% gabapentin carriedin a topical vehicle.
 8. The method of claim 7, wherein the topicalvehicle comprises a pluronic lecithin organogel.
 9. The method of claim1, wherein the pharmaceutical agent comprises a carrier containingketamine in a quantity of at least 2% and clonidine in a quantity of atleast 0.2% in concentration by volume, unbuffered.
 10. The method ofclaim 9, wherein the ketamine and clonidine each are in a concentrationrange of 2% to 4% by volume.
 11. The method of claim 1, wherein saidpoint locating step is performed by applying an electronic point finderto the subject's body and detecting a point of reduced electricalresistance relative to the electrical resistance of a surrounding bodyarea.
 12. The method of claim 1, wherein said point locating step isperformed by applying an acupuncture point finder to the subject's bodyand locating an acupuncture point.
 13. The method of claim 1, whereinsaid point locating step is performed by selecting an acupuncture pointon the subject's body.
 14. The method of claim 1, wherein said pointlocating step is performed by applying a nerve stimulator to thesubject's body and locating a point producing a muscle stimulation. 15.The method of claim 1, wherein: the iontophoretic patch ismulti-layered, comprising at least one layer containing a pharmaceuticalagent and at least one juxtaposed layer containing a pH bufferedelectrolyte; and a means for applying an iontophoretic electricalcurrent across the patch and the subject.
 16. The method of claim 15,wherein the iontophoretic patch comprises: a first layer containing apharmaceutical agent selected from the group consisting of ketamine,gabapentin, carbamazepine, clonidine, phenoxybenzamine, and nifedipine;a second layer containing a pharmaceutical agent different from theagent contained in said first layer and selected from the groupconsisting of ketamine, gabapentin, carbamazepine, clonidine,phenoxybenzamine, and nifedipine; and a third layer interposed betweensaid first and second layers and containing a pH buffered electrolyte.17. The method of claim 1, wherein the pharmaceutical agent comprises acombination of dextromethorphan, clonidine, magnesium chloride, andamantadine.
 18. A polypharmaceutical composition for treating chronicpain by producing a blockade of the initiation and propagation of thepain stimulus in the Langerhans and other neuroendocrine vascularstructures of the superficial and deep dermis, comprising: incombination, at least two pharmaceutical agents selected from the groupconsisting of an NMDA receptor blocker, a GABA receptor blocker, an AMPAreceptor blocker, a nitric oxide synthase receptor blocker, a calciumchannel blocker, an ACDP receptor blocker, a prostaglandin blocker, aleukotriene blocker, a substance P blocker, a bradykinin blocker, aneurotenin blocker, a peptide blocker, a TNF alpha blocker, asympathetic alpha 1 receptor blocker, a sympathetic alpha 2 receptorblocker, and a nonNMDA calcium-channel blocker.
 19. The composition ofclaim 18, wherein said pharmaceutical composition further comprises atopical vehicle carrying said selected agents.
 20. The composition ofclaim 19, wherein said topical vehicle comprises a pluronic lecithinorganogel.
 21. The composition of claim 18, wherein said pharmaceuticalagents are selected from the group consisting of ketamine, gabapentin,carbamazepine, clonidine, phenoxybenzamine, nifedipine, and combinationsthereof.
 22. The composition of claim 21, wherein said pharmaceuticalagents are carried in a topical vehicle comprising a pluronic lecithinorganogel.
 23. The composition of claim 18, wherein said pharmaceuticalagents comprise phenoxbenzamine, ketamine, and gabapentin in anapproximate quantity ratio of 2:5:5.
 24. The composition of claim 18,wherein the pharmaceutical agents comprise by volume approximately 2%phenoxbenzamine, 5% ketamine, and 5% gabapentin carried in a topicalvehicle.
 25. The composition of claim 24, wherein the topical vehiclecomprises a pluronic lecithin organogel.
 26. The composition of claim18, comprising a carrier containing ketamine in a quantity of at least2% and clonidine in a quantity of at least 0.2% in concentration byvolume, unbuffered, in a carrier.
 27. The composition of claim 26,wherein said ketamine and clonidine each are in a concentration range of2% to 4% by volume, in a carrier.
 28. The composition of claim 18,wherein said pharmaceutical agents comprise a combination ofdextromethorphan, clonidine, magnesium chloride, and amantadine.
 29. Amethod of treating pain by producing a blockade of the initiation andpropagation of the pain stimulus in the Langerhans and otherneuroendocrine vascular structures of the superficial and deep dermis ofa human or animal subject in need of such treatment, comprising:performing an administration step by topically administering to thesubject in need of such treatment an effective dosage of a combinationof at least two pharmaceutical agents selected from the group consistingof an NMDA receptor blocker, a GABA receptor blocker, an AMPA receptorblocker, a nitric oxide synthase receptor blocker, a calcium channelblocker, an ACDP receptor blocker, a prostaglandin blocker, aleukotriene blocker, a substance P blocker, a bradykinin blocker, aneurotenin blocker, a peptide blocker, a TNF alpha blocker, asympathetic alpha 1 receptor blocker, a sympathetic alpha 2 receptorblocker, and a non-NMDA calcium-channel blocker.
 30. The method of claim29, wherein said administration step further comprises administering theselected pharmaceutical agents in combination with a topical vehiclecarrying the selected agents.
 31. The method of claim 30, wherein saidtopical vehicle comprises a pluronic lecithin organogel.
 32. The methodof claim 29, wherein said administration step further comprisesadministering pharmaceutical agents selected from the group consistingof ketamine, gabapentin, carbamazepine, clonidine, phenoxybenzamine,nifedipine, dextromethorphan, magnesium chloride, amantadine, andcombinations thereof.
 33. The method of claim 32, wherein saidadministration step is performed by topically applying a spray of theselected pharmaceutical agents to the subject's skin.
 34. The method ofclaim 32, wherein the selected pharmaceutical agents are carried in atopical vehicle comprising a pluronic lecithin organogel.
 35. The methodof claim 34, wherein said administration step is performed by topicallyapplying a gel cream of the selected pharmaceutical agents and topicalvehicle to the subject's skin.
 36. The method of claim 29, wherein theselected pharmaceutical agents comprise phenoxbenzamine, ketamine, andgabapentin in an approximate quantity ratio of 2:5:5.
 37. The method ofclaim 29, wherein the selected pharmaceutical agents comprise by volumeapproximately 2% phenoxbenzamine, 5% ketamine, and 5% gabapentin carriedin a topical vehicle.
 38. The method of claim 37, wherein the topicalvehicle comprises a pluronic lecithin organogel.
 39. The method of claim29, wherein said administration step comprises administering ketamine ina quantity of at least 2% and clonidine in a quantity of at least 0.2%in concentration by volume, unbuffered, in a carrier.
 40. The method ofclaim 39, wherein the ketamine and clonidine each are in a concentrationrange of 2% to 4% by volume, in a carrier.
 41. The method claim 29,wherein said administration step further comprises administeringpharmaceutical agents comprising a preselected combination ofdextromethorphan, clonidine, magnesium chloride, and amantadine.
 42. Themethod of claim 41, wherein said administration step is performed bysteps comprising: first, performing a point locating step by locating apredetermined neurodermal point associated with the pain; and second,providing the preselected pharmaceutical agents by subcutaneousinjection.
 43. A method of treating pain in a human or animal subject byadministering a combination of preselected effective pharmaceuticalagents in a suitable dosage to treat a subject in need thereof,comprising: first, performing a point locating step by locating apredetermined neurodermal point associated with the pain; second,providing the preselected pharmaceutical agents for treating pain in agel patch suited for delivery by electrically driving charged ions ofthe pharmaceutical agents from the path and into the subject; third,performing an application step by applying the provided gel patch to thepredetermined neurodermal point on the subject; and fourth, performing adelivery step by delivering the selected pharmaceutical agents from thepatch to the subject by electrically driving charged ions of thepharmaceutical agents into the subject.
 44. The method of claim 43,wherein the preselected pharmaceutical agents are selected from thegroup consisting of an NMDA receptor blocker, a GABA receptor blocker,an AMPA receptor blocker, a nitric oxide synthase receptor blocker, acalcium channel blocker, an ACDP receptor blocker, a prostaglandinblocker, a leukotriene blocker, a substance P blocker, a bradykininblocker, a neurotenin blocker, a peptide blocker, a TNF alpha blocker, asympathetic alpha 1 receptor blocker, a sympathetic alpha 2 receptorblocker, a non-NMDA calcium-channel blocker, and combinations thereof.45. The method of claim 44, wherein the preselected pharmaceuticalagents are carried in a topical vehicle comprising a pluronic lecithinorganogel.
 46. The method of claim 43, wherein the preselectedpharmaceutical agents are selected from the group consisting ofketamine, gabapentin, carbamazepine, clonidine, phenoxybenzamine,nifedipine, dextromethorphan, magnesium chloride, amantadine andcombinations thereof.
 47. The method of claim 46, wherein thepreselected pharmaceutical agents are carried in a topical vehiclecomprising a pluronic lecithin organogel.
 48. The method of claim 43,wherein the preselected pharmaceutical agents comprise phenoxbenzamine,ketamine, and gabapentin in an approximate quantity ratio of 2:5:5. 49.The method of claim 48, wherein the preselected pharmaceutical agentscomprises by volume approximately 2% phenoxbenzamine, 5% ketamine, and5% gabapentin carried in a topical vehicle.
 50. The method of claim 49,wherein the topical vehicle comprises a pluronic lecithin organogel. 51.The method of claim 43, wherein the preselected pharmaceutical agentscomprises a carrier containing ketamine in a quantity of at least 2% andclonidine in a quantity of at least 0.2% in concentration by volume,unbuffered.
 52. The method of claim 51, wherein said ketamine andclonidine each are in a concentration range of 2% to 4% by volume. 53.The method of claim 43, wherein said point locating step is performed byapplying an electronic point finder to the subject's body and detectinga point of reduced electrical resistance relative to the electricalresistance of a surrounding body area.
 54. The method of claim 43,wherein said point locating step is performed by applying an acupuncturepoint finder to the subject's body and locating an acupuncture point.55. The method of claim 43, wherein said point locating step isperformed by selecting an acupuncture point on the subject's body. 56.The method of claim 43, wherein said point locating step is performed bystimulation.
 57. The method of claim 43, wherein said step of providinga gel patch further comprises: providing a multi-layered gel patchhaving at least one layer containing at least one selectedpharmaceutical agent and at least one juxtaposed layer containing a pHbuffered electrolyte; and providing a means for applying an electricalcurrent across the patch and the subject for electrically deliveringions of the selected pharmaceutical agent to the subject.
 58. The methodof claim 57, wherein the multi-layer gel patch comprises: a first layercontaining at least one pharmaceutical agent selected from the groupconsisting of ketamine, gabapentin, carbamazepine, clonidine,phenoxybenzamine, and nifedipine; a second layer containing at least onepharmaceutical agent different from an agent contained in said firstlayer and selected from the group consisting of ketamine, gabapentin,carbamazepine, clonidine, phenoxybenzamine, and nifedipine; and a thirdlayer interposed between said first and second layers and containing apH buffered electrolyte.
 59. The method of claim 57, wherein said meansfor applying an electrical current comprises: a battery supplying DCcurrent; and a means for selectively delivering the current in unipolaror bipolar mode; a means for selecting the direction of current flow;and a means for selectively delivering the current as straight DCcurrent or pulsed DC current.